Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Март 8, 2024

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in biological processes tumors. Intriguingly, mesenchymal dedifferentiated cancer cells, which are usually resistant to apoptosis traditional therapies, exquisitely vulnerable ferroptosis, further underscoring its potential treatment approach for cancers, especially refractory cancers. However, impact ferroptosis on extends beyond direct cytotoxic effect cells. induction not only inhibits but also promotes development due negative anticancer immunity. Thus, comprehensive understanding role crucial successful translation therapy from laboratory clinical applications. In this review, we provide overview recent advancements cancer, covering molecular mechanisms, functions, regulatory pathways, interactions with microenvironment. We summarize applications immunotherapy, radiotherapy, systemic therapy, well inhibition various conditions. finally discuss markers, current challenges future directions cancer.

Язык: Английский

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To metabolomics and beyond: a technological portfolio to investigate cancer metabolism

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Март 22, 2023

Abstract Tumour cells have exquisite flexibility in reprogramming their metabolism order to support tumour initiation, progression, metastasis and resistance therapies. These reprogrammed activities include a complete rewiring of the bioenergetic, biosynthetic redox status sustain increased energetic demand cells. Over last decades, cancer field has seen an explosion new biochemical technologies giving more tools than ever before navigate this complexity. Within cell or tissue, metabolites constitute direct signature molecular phenotype thus profiling concrete clinical applications oncology. Metabolomics fluxomics, are key technological approaches that mainly revolutionized enabling researchers both qualitative mechanistic model cancer. Furthermore, upgrade from bulk single-cell analysis provided unprecedented opportunity investigate biology at cellular resolution allowing depth quantitative complex heterogenous diseases. More recently, advent functional genomic screening allowed identification pathways, processes, biomarkers novel therapeutic targets concert with other allow patient stratification treatment regimens. This review is intended be guide for metabolism, highlighting current emerging technologies, emphasizing advantages, disadvantages potential leading development innovative anti-cancer

Язык: Английский

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Immune regulation through tryptophan metabolism

Experimental & Molecular Medicine, Год журнала: 2023, Номер 55(7), С. 1371 - 1379

Опубликована: Июль 3, 2023

Amino acids are fundamental units of molecular components that essential for sustaining life; however, their metabolism is closely interconnected to the control systems cell function. Tryptophan (Trp) an amino acid catabolized by complex metabolic pathways. Several resulting Trp metabolites bioactive and play central roles in physiology pathophysiology. Additionally, various physiological functions mutually regulated gut microbiota intestine coordinately maintain intestinal homeostasis symbiosis under steady state conditions during immune response pathogens xenotoxins. Cancer inflammatory diseases associated with dysbiosis- host-related aberrant inactivation aryl hydrocarbon receptor (AHR), which a several metabolites. In this review, we focus on mechanisms through converges AHR activation modulation function restoration tissue how these processes can be targeted using therapeutic approaches cancer autoimmune diseases.

Язык: Английский

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Tryptophan Metabolism Acts as a New Anti‐Ferroptotic Pathway to Mediate Tumor Growth

Advanced Science, Год журнала: 2023, Номер 10(6)

Опубликована: Янв. 10, 2023

Abstract Emerging evidence reveals that amino acid metabolism plays an important role in ferroptotic cell death. The conversion of methionine to cysteine is well known protect tumour cells from ferroptosis upon starvation through transamination. However, whether acids‐produced metabolites participate independent the pathway largely unknown. Here, authors show tryptophan serotonin (5‐HT) and 3‐hydroxyanthranilic (3‐HA) remarkably facilitate escape distinct cysteine‐mediated inhibition. Mechanistically, both 5‐HT 3‐HA act as potent radical trapping antioxidants (RTA) eliminate lipid peroxidation, thereby inhibiting Monoamine oxidase A (MAOA) markedly abrogates protective effect via degrading 5‐HT. Deficiency MAOA renders cancer resistant treatment. Kynureninase (KYNU), which essential for production, confers death, whereas 3‐hydroxyanthranilate 3,4‐dioxygenase (HAAO) significantly blocks mediated inhibition by consuming 3‐HA. In addition, expression level HAAO positively correlated with peroxidation clinical outcome. Together, findings demonstrate works a new anti‐ferroptotic promote growth, targeting this will be promising therapeutic approach

Язык: Английский

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Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition

Nature Cell Biology, Год журнала: 2024, Номер 26(1), С. 124 - 137

Опубликована: Янв. 1, 2024

Язык: Английский

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SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via induction of NAD+ depletion-dependent activation of ATF3

Redox Biology, Год журнала: 2024, Номер 69, С. 103030 - 103030

Опубликована: Янв. 3, 2024

Ferroptosis is a type of programmed cell death resulting from iron overload-dependent lipid peroxidation, and could be promoted by activating transcription factor 3 (ATF3). SIRT1 an enzyme accounting for removing acetylated lysine residues target proteins consuming NAD+, but its role remains elusive in ferroptosis ATF3. In this study, we found was activated during the process RSL3-induced glioma ferroptosis. Moreover, aggravated activator SRT2183, suppressed SIRT inhibitor EX527 or when silenced with siRNA. These indicated sensitized cells to Furthermore, expressional upregulation nuclear translocation Silence ATF3 siRNA attenuated increases ferrous downregulation SLC7A11 GPX4 depletion cysteine GSH. Thus, inducting activation. Mechanistically, activation reinforced decline NAD+ FK866 that inhibit NAD + synthesis via salvage pathway, intracellular maintained at higher level supplement exogenous NAD+. Notably, caused RSL3 enhanced further inhibited EX527. consumption Finally, inducing reactive oxygen species-dependent AROS. Together, our study revealed AROS sensitizes ATF3-dependent inhibition GPX4.

Язык: Английский

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Thirty years of NRF2: advances and therapeutic challenges

Nature Reviews Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Язык: Английский

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Indole‐3‐Lactic Acid Inhibits Doxorubicin‐Induced Ferroptosis Through Activating Aryl Hydrocarbon Receptor/Nrf2 Signalling Pathway

Journal of Cellular and Molecular Medicine, Год журнала: 2025, Номер 29(2)

Опубликована: Янв. 1, 2025

ABSTRACT The clinical application of doxorubicin (DOX) is limited due to its cardiotoxicity, which primarily attributed interaction with iron in mitochondria, leading lipid peroxidation and myocardial ferroptosis. This study aimed investigate the role gut microbiota‐derived metabolite, indole‐3‐lactic acid (ILA), mitigating DOX‐induced cardiotoxicity (DIC). Cardiac function, pathological changes, ferroptosis were assessed vivo. cardioprotective effects mechanisms ILA explored using multi‐omics approaches, including single‐nucleus RNA sequencing (snRNA‐seq) bulk RNA‐seq, further validated Nrf2 knockout mice. findings revealed that DOX treatment disrupted microbiota, significantly reducing levels tryptophan metabolite ILA. In DIC models, supplementation markedly improved cardiac reduced collagen deposition, mitigated atrophy. snRNA‐seq analyses indicated played a crucial Experimental data demonstrated decreased both mice DOX‐treated H9C2 cells, evidenced by restoration GPX4 SLC7A11 reduction ACSL4. Mechanistically, functions as ligand for aryl hydrocarbon receptor (AhR), upregulation expression. protective against abolished silencing AhR. Moreover, beneficial on eliminated Nrf2‐deficient conclusion, exerts therapeutic inhibiting through activation AhR/Nrf2 signalling pathway. Identifying microbial could offer viable strategies DIC.

Язык: Английский

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IL4i1 and IDO1: Oxidases that control a tryptophan metabolic nexus in cancer

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(6), С. 104827 - 104827

Опубликована: Май 23, 2023

Regulated tryptophan metabolism by immune cells has been associated with the promotion of tolerance and poor outcomes in cancer. The main focus research centered on local depletion IDO1, an intracellular heme-dependent oxidase that converts to formyl-kynurenine. This is first step a complex pathway supplying metabolites for de novo NAD+ biosynthesis, 1-carbon metabolism, myriad kynurenine derivatives which several act as agonists arylhydrocarbon receptor (AhR). Thus, express IDO1 deplete while generating downstream metabolites. We now know another enzyme, secreted L-amino acid IL4i1 also generates bioactive from tryptophan. In tumor microenvironments, have overlapping expression patterns, especially myeloid cells, suggesting two enzymes control network tryptophan-specific metabolic events. New findings about shown both generate suite suppress oxidative cell death ferroptosis. within inflammatory environments, simultaneously essential amino depletion, AhR activation, suppression ferroptosis, biosynthesis key intermediates. Here, we summarize recent advances this field, focusing speculate inhibition remains viable adjuvant therapy solid tumors, effects must be accounted for, potentially may need inhibited at same time produce positive cancer therapy. 20 proteinogenic acids sustain cellular biochemistry by: (i) translation, (ii) source carbon skeletons nitrogen energy generation nucleotide (iii) "shuttles" move molecules different compartments tasks such malate-aspartate shuttle or methionine major methyl donor 1-carbon-folate cycle. Several dedicated additional functions precursors signaling (neurotransmitters), cofactors (heme, glycine), redox protective glutathione (from glycine, cysteine, glutamate). Because these diverse functions, balance their sources synthesis, transport, scavenging protein sinks therefore constantly monitor deficiencies excesses all acids. An facet concerns biochemical where regulated enzyme consumes distinct products. setting, events occur simultaneously: can become limiting, triggering defenses including increased reduction activation autophagy (and related measures) products modulatory effects. define "regulated" here specific, induced activity metabolizing via cytokines, pathogen products, other pathways, acquisition not normally present type interest. case latter, many patterns differ origin, presumably way obtain resources growth evade control. acid-metabolizing cytokines are arginases (ARG1 cytoplasm ARG2 mitochondria), oxidases (indole, 2,3 dioxygenase), TDO2 (tryptophan dioxygenase) (Interleukin 4-induced 1, oxidase) (1Murray P.J. Amino auxotrophy system immunological nodes.Nat. Immunol. 2016; 17: 132-139Google Scholar). 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Язык: Английский

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Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes

Journal for ImmunoTherapy of Cancer, Год журнала: 2023, Номер 11(6), С. e006728 - e006728

Опубликована: Июнь 1, 2023

Background Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-dioxygenase (TDO) are enzymes catabolizing the essential amino acid tryptophan into kynurenine. Expression of these is frequently observed in advanced-stage cancers associated with poor disease prognosis immune suppression. Mechanistically, respective roles shortage kynurenine production suppressing immunity remain unclear. Kynurenine was proposed as an endogenous ligand for aryl hydrocarbon receptor (AHR), which can regulate inflammation immunity. However, controversy remains regarding role AHR IDO1/TDO-mediated suppression, well involvement In this study, we aimed to clarify link between IDO1/TDO expression, pathway activation Methods expression analyzed by RT-qPCR western blot analysis cells engineered express IDO1/TDO, or cultured medium mimicking catabolism IDO1/TDO. vitro differentiation naïve CD4 + T regulatory (Tregs) compared isolated from mice bearing different Ahr alleles a knockout , without Results We confirmed that activated HEK-293-E cells, measured induction target genes. Unexpectedly, also overexpressed on expression. overexpression did not depend but triggered deprivation. Multiple human tumor cell lines dependent general control non-derepressible 2 (GCN2), strongly sensitized pathway. As result, other catabolites, weak agonists normal conditions, induced genes tryptophan-depleted conditions. Tryptophan depletion increased uptake increasing SLC7A5 (LAT1) GCN2-dependent manner. deprivation potentiated Treg allele affinity similar AHR. Conclusions sensitizes inducing cellular uptake. catabolites such more potently activate AHR, promoted. Our results propose molecular explanation combined mediating IDO1/TDO-induced

Язык: Английский

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